[10-24-2011] The U.S. Food and Drug Administration (FDA) has reviewed the results from two FDA-sponsored epidemiological studies that evaluated the risk of neuropsychiatric adverse events associated with the smoking cessation drug Chantix (varenicline).

Facts about Chantix (varenicline)

A prescription medicine used to help adults quit smoking

Increases the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.

Works by blocking the effects of nicotine (from smoking) on the brain.1

From approval in May 2006 through July 2011, approximately 21.8 million Chantix prescriptions were dispensed and approximately 8.9 million patients received Chantix prescriptions from U.S. outpatient retail pharmacies.2

Neither study found a difference in risk of neuropsychiatric hospitalizations between Chantix and nicotine replacement therapy (NRT; e.g., NicoDerm patches). However, both studies had a number of study design limitations, including only assessing neuropsychiatric events that resulted in hospitalization, and not having a large enough sample size to detect rare adverse events (see Data Summary below for more information). Although these two studies did not suggest an increased risk of neuropsychiatric events that result in hospitalization, they do not rule out an increased risk of other neuropsychiatric events with Chantix.

Healthcare professionals and patients should continue to follow the recommendations in the physician label and the patient Medication Guide, and to monitor for neuropsychiatric symptoms when prescribing or using Chantix. Based on FDA’s assessment of currently available data, the Agency continues to believe that the drug’s benefits outweigh the risks and the current warnings in the Chantix drug label are appropriate.

The risk of serious neuropsychiatric events with Chantix is currently highlighted in the Boxed Warning and Warnings and Precautions section of the physician label and in the patient Medication Guide. Such events can include changes in behavior, hostility, agitation, depressed mood, and suicidal thoughts or actions. These warnings were based on postmarketing reports describing changes in mood and behavior during and after Chantix use (see 2008 Public Health Advisory and 2009 Public Health Advisory).

FDA is continuing to evaluate the risk of neuropsychiatric events with Chantix. The drug manufacturer is conducting a large safety clinical trial of Chantix to assess neuropsychiatric adverse events, and results from this study are expected in 2017.

Some patients have experienced changes in behavior, hostility, agitation, depressed mood, and suicidal thoughts or actions while using Chantix to help them quit smoking. Some patients had these symptoms soon after they began taking Chantix, and others developed them after several weeks of treatment, or after stopping Chantix.

Before taking Chantix, patients should inform their healthcare professional if they have ever had depression or other mental health problems.

If a patient develops agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for them, or if a patient develops suicidal ideation or behavior, they should immediately discontinue Chantix and report these symptoms to their healthcare professional.

Patients should read the Medication Guide that they get along with their Chantix prescription. It explains the risks associated with the use of Chantix.

Patients should report serious side effects from the use of Chantix to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page.

Healthcare professionals should ask patients about any history of psychiatric illness, especially depression, prior to initiating treatment with Chantix.

Healthcare professionals should advise patients and caregivers that the patient should immediately stop taking Chantix and contact a healthcare professional if agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior while taking or shortly after discontinuing Chantix.

Healthcare professionals should encourage patients to read the Medication Guide they receive along with their Chantix prescription.

Healthcare professionals should report adverse events involving Chantix to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page

FDA sponsored two observational studies of neuropsychiatric adverse events with Chantix. One was conducted by the Department of Veterans Affairs’ (VA) Center for Medication Safety (VAMedSAFE), and the other by the Department of Defense’s (DoD) U.S. Army Medical Command’s Pharmacovigilance Center (PVC; hereafter referred to as the “DoD study”).

The VA study was a retrospective cohort study to evaluate the incidence of mental health hospitalizations among veterans using Chantix or nicotine replacement therapy (NRT). Patients starting Chantix or NRT between May 1, 2006 and September 30, 2007, but with no Chantix or NRT use in the previous year, were selected and matched in a 1:1 ratio by use of propensity scores (reflecting demographic characteristics, comorbidities, and psychiatric history). Propensity score matching is a method of balancing patient characteristics between the treatment groups being compared. The study’s main outcome was psychiatric hospitalization, with a coded primary discharge diagnosis for one of a number of psychiatric conditions, including drug-induced mental disorders, schizophrenic disorders, other psychotic disorders, depression, suicide attempts, and other mood disorders. Because the spontaneous adverse event reports for Chantix suggested a relatively short time to onset for psychiatric reactions, psychiatric hospitalizations for selected psychiatric diagnoses were assessed for 30 days after a prescription fill for Chantix or NRT.

The VA study population included 14,131 Chantix users and an equal number of NRT users. Among these patients, there were 16 psychiatric hospitalizations in Chantix-treated patients, and 21 in NRT patients. A Cox proportional hazards analysis showed no statistically significant difference in the risk of psychiatric hospitalization for Chantix users compared to NRT users (hazard ratio [HR] for Chantix/NRT = 0.76; 95% confidence interval [CI] 0.40-1.46). A complementary analysis in a prevalent user cohort of patients who had used NRT in the past before initiating Chantix or refilling an NRT prescription also showed no statistically significant difference in psychiatric hospitalizations between the two treatment groups. Also, the results using time periods longer than 30 days after a prescription fill were similar.

The DoD study was also a retrospective cohort study comparing the acute (30-day) rates of hospitalizations for neuropsychiatric adverse events among new users of Chantix (n=19,933) and NRT patch (n=15,867) who started therapy from August 1, 2006 to August 31, 2007 in the Military Health System. Patients were drawn from active duty military personnel, military retirees, and the dependents of either. Chantix users were matched using propensity scores to NRT users, with subgrouping by concomitant use of the prescription smoking cessation drug bupropion. After propensity score matching, there were 11,978 Chantix users and an equal number of NRT users in the study sample. The main outcome was a primary hospital discharge diagnosis for a neuropsychiatric condition. The following neuropsychiatric diagnoses were identified using ICD-9 codes: drug-induced mental disorders, transient mental disorders, schizophrenia, episodic and mood disorders, delusional disorders, other nonorganic psychoses, anxiety disorders, personality disorders, posttraumatic stress disorder (PTSD), depressive disorders, and suicide attempt.

In the DoD study’s propensity score matched samples, there were 18 psychiatric hospitalizations among Chantix users and 16 among NRT users. A Cox proportional hazard analysis did not show a statistically significant difference (HR for Chantix/NRT = 1.13; 95% CI 0.57-2.21). There was also no significant difference in psychiatric hospitalizations for Chantix users compared to NRT users when patients with concomitant bupropion use were excluded (HR = 0.91; 95% CI 0.39-2.14). Most (43) of the 55 neuropsychiatric hospitalizations (18 of the 23 Chantix events and 25 of the 32 NRT events) occurred in patients with a neuropsychiatric diagnosis in the year preceding the Chantix/NRT prescription fill, although such patients were a minority of the cohorts. Among patients with a neuropsychiatric diagnosis in the preceding year, 0.7% of Chantix users and 1.4% of NRT users were hospitalized for psychiatric care.

A strength of both studies was the inclusion of patients with pre-existing psychiatric disorders, since these patients were typically excluded from the clinical trials conducted with Chantix before it was approved (i.e., in premarketing trials).

Although neither study found a measurable increase in psychiatric hospitalizations with Chantix versus NRT, these results should be interpreted with the limitations of both studies in mind. The sample sizes in both studies were too small to assess rare, idiosyncratic events. Focusing on psychiatric hospitalizations is a useful approach for assessing the risk of serious neuropsychiatric adverse events, but it does not allow an assessment of less severe neuropsychiatric events that did not result in a psychiatric hospitalization (in the periods studied). Although the studies did not find a difference in psychiatric hospitalization risk between Chantix and NRT, they do not exclude the possibility that both treatments carry a similar risk. In addition, the VA study did not include PTSD as a reason for psychiatric hospitalization; one published report suggested that patients with PTSD may be more susceptible to the neuropsychiatric adverse effects of Chantix.3 Also, the DoD study only assessed a 30-day risk period following the fill date of the first qualifying prescription for Chantix or NRT and did not evaluate the rate of neuropsychiatric hospitalizations occurring over a longer duration following a Chantix prescription fill.

Overall, FDA has determined that the current warnings in the Chantix drug label, based on postmarketing surveillance reports, remain appropriate.

FDA is continuing to evaluate the risk of neuropsychiatric adverse events with Chantix. The manufacturer of Chantix, Pfizer, is conducting a large safety clinical trial of Chantix to assess neuropsychiatric adverse events as outcomes. Results from this trial are expected in 2017.